This program seeks a comprehensive understanding of the structure and function of the spleen, the bone marrow, and other hematopoietic tissues, using electron and light microscopy, tissue culture, immunocytochemistry, autoradiography and related morphologic and hematologic techniques, on tissues from experimental mutant mice, other laboratory and domestic animals, and human beings. Focus has been upon cellular associations and upon the stroma and vasculature and their regulation of hematopoiesis. Several projects have been designed to clarify and amplify our discovery of large-scale activation and differentiation of the reticular cell stroma of spleen (and bone marrow) with consequences on hematopoietic microenvironments and the control of erythropoiesis, the protection of blood and hematopoietic cells from parasites, control of the filtration beds of the spleen and upon blood flow through the spleen, and upon the development of effective blood-spleen barriers. These include: the splenic and marrow management of heat-damaged isologous erythrocytes, regeneration of the spleen with formation of splenules, and the blood-white pulp barrier. The selective pathways that B cells and subsets of T cells take through spleen and other tissues shall be charted by autoradiography. The mechanisms by which the spleen contains (or, in some cases, intensifies) infectious disease shall be further studied in malaria and in S. typhimurium infections. Electron microscopic cytochemistry, using selective markers distinctive for cell type (B cell, subsets Lyt-2+ and L3T4+ of T cells, monocyte-macrophage, interdigitating cell and reticular cell) are being widely applied to both experimental and human tissues. Human spleen is being received from an international network of colleagues and studied electron microscopically and cytochemically. Work is in progress on the spleen in sickle cell disease and the thalassemias, correlating findings with those in animal models.